Cancer is the second leading cause of death in United States and new therapeutics are desperately needed to combat the disease. In 1985, the RET (RE-arranged during Transfection) gene was identified as a novel oncogene activated through chromosomal rearrangement. Since then, RET has been identified as a driving oncogene in several cancers, especially for medullary thyroid cancer (MTC). Due to the challenges of identifying a selective RET inhibitor, a treatment for MTC is still an unmet medical need. In an effort to develop a RET kinase inhibitor, a picomolar RET/VEGFR2 clinical candidate has been developed and is currently in preclinical studies. However, the inhibition of VEGFR2 is associated with vascular on-target dose-limiting toxicities, including hypertension in patients for most VEGFR2 inhibitor drugs. We wish to further develop an inhibitor by removing VEGFR2 activity and improving overall selectivity in the kinome, thereby achieving maximal/or complete inhibition of the RET-signaling pathway in patients. We will utilize validated computational models of RET and VEGFR2, fragment-based screening, and potential X-ray crystal structural information to develop a clinical candidate with >30 times RET selectivity over VEGFR2. The resulting selective RET inhibitor could maximally block the RET signaling pathway and will increase MTC survival from months to multiple years.